ANTIUCROBIAL AGENTS AND CHEMOTHERAPY, JUly 1981, p. 88-97 0066-4804/81/070088-10$02.00/0 Vol. 20, No. 1 Clinical Evaluation of Moxalactam W. K. LIVINGSTON, A. M. ELLIOTT, W. E. DISMUKES, C. K. AVENT, AND C. G. COBBS* Department ofmedicine, University ofalabama School ofmedicine, Birmingham, Alabama 35294 Received 9 January 1981/Accepted 30 March 1981 We investigated the clinical efficacy of moxalactam for treatment of a variety of infectious disorders in 50 patients (38 males and 12 females). Patient ages ranged from 8 days to 98 years, with a median of 66 years. Infectious disorders were confirmed by isolation of etiological bacteria in all patients. Thirty-eight patients had gram-negative bacillary disease, nine had pneumococcal infection, and three had disorders caused by staphylococci or streptococci. Twenty-three patients had pneumonia, 17 had bacteremic diseases other than pneumonia, and 10 had miscellaneous infectious diseases. The overall efficacy of moxalactam was excellent. Forty-eight patients were cured by clinical criteria, and 45 were cured by bacteriological criteria. A total of 19 adverse reactions were associated with the use of moxalactam in 18 patients, but none were severe and only one necessitated discontinuation of treatment. Moxalactam promises to be an important addition to our therapeutic armamentarium, especially for therapy of gramnegative bacillary infections. Moxalactam disodium (LY127935) is a new semisynthetic beta-lactam antimicrobial agent. It is a 1-oxa-beta-lactam antibiotic; an oxygen molecule has been substituted for sulfur in the cephem nucleus. A previous communication from this laboratory reported the results of in vitro susceptibility testing with this agent against a large number of clinical isolates of gram-negative bacilli (6). During the last 2 years, a trial of the efficacy of moxalactam has been carried out in patients at this institution; the results are described here. MATERIALS AND MlEHODS Patients who were hospitalized at The University Hospital of the University of Alabama Medical Center and at the Birmingham Veteran's Administration Medical Center, Birmingham, Ala., were available for study (one patient was treated at an outside hospital). In most instances, medical house staff serving at these institutions identified patients suspected of fulfilling criteria for entry into the study. The patients were then interviewed by one of us (W.K.L.); if criteria were met, informed consent was solicited and obtained. This was not a controlled study; patients were selected and treated consecutively, and no other antimicrobial regimen was used. Underlying diseases were determined by exaniination of the patients and their medical records. All of the following criteria were necessary for enrollment in the study: (i) suspected bacterial infection and anticipated isolation of the etiological microorganism(s) from either blood, spinal fluid, or other normally sterile fluid or from inflammatory exudate; (ii) no prior antimicrobial agent(s) effective against the etiological bacteria; (iii) no history of allergy to ceph- 88 alosporin-type agents and no history of an immediate hypersensitivity reaction to penicillins; (iv) nonpregnant female; (v) no identifiable risk of life-threatening pseudomonas disease (for example, patients with acute leukemia and granulocytopenia); (vi) no evidence of prosthetic valve endocarditis; and (vii) no evidence of central nervous system infectious disease (patient 49 represents an exception; see below). For retention in the study, the etiological bacteria had to be isolated, identified, and susceptible to moxalactam by disk diffusion testing. Initially, bacteria exhibiting zone sizes of 18 mm or greater were considered susceptible. Later, during the course of the study, criteria were changed by the manufacturer, therefore, a zone size of-23 mm was used to define susceptible organi ms, and a zone of 15 to 22 mm was used to identify intermediate ones. Thirteen strains considered susceptible were then switched to the intermediate category. Two patients with polymicrobial infectious disorders were treated with moxalactam, even though one of the bacteria was resistant to it. Patient 16, who had osteomyelitis, was infected by two bacteria, a Pseudomonas aeruginosa resistant to moxalactam and a Serratia marcescens susceptible to moxalactam. Patient 22, with gram-negative bacillary pneumonia, had Haemophilus influenzae and Acinetobacter calcoaceticus isolated from sputum. The H. influenzae isolate was intermediate in susceptibility to moxalactam, and the A. calcoaceticus isolate was resistant. Moxalactam (supplied by Lilly Research Laboratories, Indianapolis, Ind.) was usually administered parenterally via scalp vein infusion except in two patients (42 and 44) who were discharged and treated at home with intramuscular drug. The dosage ranged from 10 to 146 mg/kg per day (mean dose, 50 mg/kg per day). The drug was generally given three times daily and infused over 20 to 40 min diluted in approximately 50 ml of either normal saline or 5% dextrose in
VOL. 20, 1981 water. Dosage adjustment in patients with renal insufficiency was patterned after guidelines formulated for cefamandole (14). Serum drug levels were not obtained. Toxicity was monitored by daily examination of patients and by determination of laboratory tests before initiation of therapy and at intervals during and after completion of therapy. Any abnormality detected was followed up if possible with additional tests in an attempt to determine the etiology and subsequent trend of the abnormality. No antimicrobial therapy was administered after discontinuation of moxalactam. Cultural techniques. Blood cultures were obtained before initiation of antimicrobial agents in all patients admitted to the study. With sterile technique, 10 ml of blood was obtained by venipuncture; 5 ml was inoculated into each of two Bactec bottles containing 30 ml of aerobic and anaerobic blood culture medium, respectively. Two separate venipunctures to inoculate a total of four bottles were performed on each patient. In addition, in all patients with lower respiratory tract infection, expectorated sputum or tracheal aspirate for Gram-stained smears and cultures was obtained. In patients with urinary tract infection, urine was examined microscopically and cultured quantitatively. In patients with cellulitis, material from sites of local inflammation was obtained for Gram stains and cultures; in instances where there was no apparent focus of inflammation, sterile saline was injected beneath the skin and aspirated, and this material cultured. One patient with liver abscess had pus aspirated at the time of surgery. In all patients, we attempted to obtain cultures of the original site after completion of treatment. If such materials were unobtainable, blood cultures were drawn. Susceptibility testing. Moxalactam susceptibility of all bacterial pathogens was determined by disk diffusion technique. To define the minimal inhibitory concentration (MIC) and minimal bactericidal concentration, a microtiter technique was used (2). In some instances, the antimicrobial activity of serum (1) was assayed against the infectious bacteria while the patient was receiving moxalactam. Efficacy of therapy. The efficacy of therapy was evaluated by clinical and bacteriological outcome. Patients were followed by one of us (W.K.L.) on a regular basis during and after completion of therapy. The following criteria were used as indications for bacteriological cure: for patients with pneumonia, eradication of the etiological bacteria from sputum, if available; for patients with bacteremia, a sterile blood culture; for patients with urinary tract infection, a sterile urine culture; for patients with osteomyelitis, absence of the etiological bacteria from bone aspirates; for soft tissue infection, absence of the etiological bacteria from pus if present or, if the wound had healed, sterile blood cultures; for patients with meningitis, sterile cerebrospinal fluid cultures. Criteria for clinical cure were as follows: for patients with pneumonia, defervescence and resolution of symptoms and signs of lower respiratory tract infection together with roentgenographic improvement or resolution; for patients with bacteremia, improvement or resolution of symptoms and signs of sepsis. Clinical CLINICAL EVALUATION OF MOXALACTAM 89 cure was documented in patients with osteomyelitis when signs of local inflammation disappeared, sinus tract drainage resolved, and evidence of healing was present roentgenographically. Patients with urinary tract infection were considered cured clinically when symptoms of flank pain, fever, toxicity, dysuria, frequency, and urgency had resolved. RESULTS Fifty patients were treated between April 1978 and December 1980. There were 38 males and 12 females; ages ranged from 8 days to 98 years, with a median of 66 years. The duration of therapy ranged from 4 to 98 days, with a median of 12 days. Dosage varied from 10 to 146 mg/kg per day. Bacterial isolates were obtained in all patients. Twenty-three patients had pneumonia, 17 had bacteremic disease other than pneumonia, 2 had urinary tract infection, 4 had soft tissue infection, and 4 had other infectious disorders. No patient with an infectious disorder caused by anaerobic bacteria alone or in combination with aerobic species was treated. Table 1 describes, clinical and bacteriological outcomes for all patients. Table 2 summarizes the outcome of 23 patients with pneumonia. All patients were cured clinically. Two of the patients (4 and 37) had bacteremic disease, whereas the remainder were diagnosed by sputum culture. Transtracheal aspirations were not performed. The etiological microorganisms of nonpneumococcal pneumonias were determined by blood culture in one patient, by pure culture from sputum in five patients, by abundant growth from one sputum culture in four patients, and by abundant growth from more than one sputum culture in four patients. Follow-up sputum cultures were obtained in 21 patients, and in 19 the suspected etiological microorganisms were eliminated. Two patients were considered bacteriological failures. Despite clinical and radiological improvement in patient 4, bronchial washings and sputum continued to grow pneumoniae susceptible to moxalactam. The blood cultures which were initially positive for that microorganism were subsequently sterile. Patient 47, who developed gram-negative pneumonia after admission for respiratory failure, improved clinically and radiologically during treatment but continued to produce small amounts of sputum from which Proteus mirabilis was recovered after discontinuation of moxalactam. Seventeen patients with bacteremic disorders other than pneumonia were treated with moxalactam, and 16 were considered clinical cures
CIA UV LIVINGSTON ET AL. ANTIMICROB. AGENTS CHEMOTHER. TABLE 1. Outcome of bacterial infections in 50 patients treated with moxalactam Bacteriological results Clinical results No. of patients Failure Unevalu- Failure Unevaluable ~ ue Fiue able Pneumonia 23 19 2 2 23 Other infectious disorders with 17 17 16 1 bacteremia Other infectious disorders without 10 9 la 9 la bacteremia Total 50 45 2 3 48 1 1 a Drug discontinued because of hypersensitivity reaction. (Table 3). Bacteremic illnesses included pyelonephritis in eight patients and one patient each with intraabdominal abscess, mediastinitis, thermal injury, decubitus ulcer, hepatic abscess, perinephric abscess, infective endocarditis, ulcerating colonic carcinoma, and septic phlebitis. Patient 15, who was admitted with "locked-in" syndrome after cerebral infarction, developed urinary tract infection and bacteremia with Pseudomonas aeruginosa. Both blood and urine cultures became sterile during moxalactam therapy, but on the 11th day of treatment, while ostensibly improving, the patient died suddenly. No post-mortem examination was performed. In all other patients in this group, follow-up cultures were obtained which documented eradication of the etiological microorganism in each. Table 4 provides information on the patients with infectious disorders without documented bacteremia. In all patients except 25 and 31, the suspected etiological microorganisms were cultured on more than one occasion, and often on several cultures during extended periods of time. Patients 28 and 31, with nonbacteremic urinary tract infection, were cured. All four patients with soft tissue infections (20, 23, 25, and 44) were cured bacteriologically and clinically. Patients 23 and 44 required surgical intervention, whereas patients 20 and 25 received skin grafts to the involved sites after eradication of their infections. Three patients were treated with moxalactam for osteomyelitis (16, 27, and 42), and one infant (49) required the drug for treatment of gramnegative meningitis (Table 4). Patient 16 had traumatic resection of 10 cm of his right tibia as a result of a motorcycle accident with subsequent infection by S. marcescens and P. aeruginosa. The serratia was susceptible to moxalactam and resistant to aminoglycosides, and the pseudomonas was resistant to moxalactam and susceptible to amikacin. Initial treatment at another institution for 7 weeks with cefoxitin and chloramphenicol was unsuccessful. After prolonged therapy with moxalactam and amikacin, the patient underwent bone graft and recovered. Patient 27 with thalassemia and vascular insufficiency presented with osteomyelitis ofher right great toe caused by Staphylococcus aureus. Therapy with moxalactam, which resulted in sterilization of drainage, had to be terminated prematurely because of drug fever. Patient 42 sustained severe trauma to the right tibia and required prolonged antimicrobial therapy directed against several gram-negative bacilli cultured from the wound, among which was a multiply resistant strain of P. maltophilia susceptible only to moxalactam. Patient 42 also required aminoglycosides for the treatment of P. aeruginosa resistant to moxalactam. Patient 49 developed neonatal meningitis caused by Escherichia coli resistant to ampicillin, chloramphenicol, carbenicillin, and tetracycline. After 3 days of therapy with gentamicin, E. coli could still be isolated from the cerebrospinal fluid, and the patient was unimproved clinically. Moxalactam was then added, and subsequently clinical improvement was rapid with sterilization of the cerebrospinal fluid in 2 days. Adverse reactions to moxalactam. Eleven patients developed abnormal liver function tests during therapy with moxalactam (Table 5). In seven patients, the only abnormality was a rise in the serum glutamic oxalacetic transaminase (SGOT). None of these patients received intramuscular injections. In three patients, only the serum alkaline phosphatase concentration was increased; in one patient, both SGOT and alkaline phosphatase levels rose above normal during moxalactam therapy. No patient developed an abnornal serum bilirubin level. Five of the patients with increased SGOT and two patients with elevated alkaline phosphatase demonstrated only mildly abnormal values, i.e., less than twice the normal levels. In those patients who had repeat studies after completion of therapy, the abnormal values returned to normal. Patient 43 had transient elevation of SGOT after surgery, thought to be caused by halothane. The serum SGOT obtained 4 days after moxalactam
VOL. 20, 1981 CLINICAL EVALUATION OF MOXALACTAM 91 TABLE 2. Patients with pneumonia Days of Result Bceilg-Ciia Patient Age (yr) Underlying disessea Organism isolatedb treat- Bactolog- Clinica no. ~~~~~~~~~~~~~~~ment 4 54 COPD, alcoholism, 10 Failure smoking pneumoniae (S, B) 5 66 Anemia, chronic renal S. pneumoniae 7 failure, CHF, diabetes 9 69 12 36 13 37 17 88 mellitus Pneumoconiosis Smoking COPD, hypertension 18 53 COPD 22 60 COPD, GI bleeding 24 71 COPD, CHF, prostatic nodule 26 60 Fractured rib 29 82 COPD, anemia, prostatic hypertrophy 32 45 Astrocytoma (chronic), CHF, diabetes mellitus 34 54 CHF, mild renal insufficiency, obesity 35 73 37 68 38 91 39 88 40 50 Cerebral infarction, old myocardial infarction CVA, chromophobe adenoma COPD COPD, hypertension Diabetes mellitus 45 66 Malnutrition, metastatic 46 64 squamous cell carcinoma (lung), tuberculosis, alcoholism GI bleeding, secondary uremia, seizure disorder, acute renal failure 47 64 CHF, peptic ulcer disease, interstitial lung disease 48 98 CHF, COPD, prostate nodule 50 67 Diabetes mellitus S. pneumoniae S. pneumoniae S. pneumoniae Haemophilus influenzae Serratia marcescens Acinetobacter calcoaceticus H. influenzae pneumoniae Staphylococcus aureus Pseudomonas fluorescens P. aeruginosa Proteus mirabilis Enterobacter aerogenes pneumoniae Serratia marcescens (S, B, U) pneumoniae H. influenzae Proteus mirabilis Citrobacter diversus pneumoniae Pseudomonas aeruginosa Proteus mirabilis Klebsiellapneumoniae Serratia marcescens, group B 10 5 4 8 12 10 8 7 10 10 14 7 13 10 8 11 10 Follow-up culture not obtained 7 Follow-up culture not obtained 14 Failure 11 9 a COPD, Chronic obstructive pulmonary disease; CHF, congestive heart failure; GI, gastrointestinal; CVA, cerebrovascular accident. b S, Sputum; B, blood; U, urine. therapy ended was normal. Patient 40, who had pneumonia, demonstrated an increase in SGOT from 18 to 177 IU/liter and a rise in alkaline phosphatase from 202 to 920 IU/liter during 11 days of moxalactam therapy. The patient was asymptomatic at the completion of antibiotic therapy and was lost to follow-up. Patient 12, with nonbacteremic pneumococcal pneumonia, had a normal serum SGOT before therapy; on the day therapy was discontinued, the value
TABLE 3. Other infectious disorders with bacteremia atient Age (yr) Underlying diwea Type or site of in- Rg* Resukt Days of fection Orgam treatment Bacterio-. logical 1 31 Gunshot wound, Abdominal Serratia 14 renal failure abscess marcescens (B, W) 2 25 Mediastinitis Operative S. marcescens (B) 13 wound 3 25 Burn, 55% body Burns S. marcescens (B) 14 surface area 6 71 COPD, carcinoma Pyelonephritis Klebsiella 14 of prostate and pneumoniae (B, lungs, diabetes U, W) mellitus 7 76 Organic brain Decubitus ulcers Proteus mirabilis 20 syndrome, atrial (B, W) fibrillation 8 55 Multiple myeloma Pyelonephritis S. marcescens (B, 31 U) 10 80 Polyclonal Pyelonephritis Escherichia coli 14 gamnmopathy (B, U) 11 47 Diabetes mellitus, Pyelonephritis E. coli (B, U) 15 chronic renal insufficiency 14 79 Pyelonephritis Enterobacter 15 aerogenes (B, U) 15 59 Cerebral infarction, Pyelonephritis Pseudomonas 11 Death GI bleeding aeruginosa (B, U) 19 36 GI bleeding, Hepatic abscess Kiebsiella 29 chronic pneumoniae (B, pancreatitis, W) diabetes mellitus Viridans (B) Enterobacter cloacae Lactobacillu sp. (B) Diphtheroids 21 47 Renal insufficiency, Perinephric S. marcescens (B, 21 carcinoma of abscess W) cervix 30 58 Rheumatoid Pyelqnephritis Escherichia coli 13 arthritis (li) Pseudomonas fluorescens (B) pneumoniae (B) 33 84 Chronic mild renal Pyelonephritis Proteus mirabilis 28 insufficiency, Endocarditis (U) calcific aortic E. coli (U) stenosis with K. pneumoniae (U) CHF, history of Staphylococcus GI bleeding aureus (B) 36 73 Pyelonephritis E. coli (B, U) 8 41 80 CHF, hypertension, GI tract E. coli (B) 17 carcinoma of K. pneumoniae (B) colon, aortic stenosis, anemia 43 43 Epidural tumor Septic phlebitis Serratia 14 marcescens (B, W) a See Table 2. b B, Blood; W, wound; U, urine. 92
VOL. 20, 1981 CLINICAL EVALUATION OF MOXALACTAM 93 TABLE 4. Other infectious disorders without bacteremia Days Result Patient Underlying dis- Type orsite Organism iso- of no. ease of infection lateda treat- Bacterio- Clinical ment logical 16 15 Trauma Osteomyelitis Serratia Debridement 98 tibia and marcescens fibula Pseudomonas aeruginosa 20 56 Alcoholism, Soft tissue, S. marcescens None 47 schizophrenia left hip 23 60 Peripheral Soft tissue, Escherichia coli Debridement 9 neuropathy left foot group B 25 72 Peripheral Soft tissue, Citrobacter None 12 vascular right ankle diversus disease 27 25 Thalassemia minor, sclerodactyly with Reynaud's, rheumatic valvular disease 28 64 Indwelling urinary catheter, Huntington's chorea, glaucoma 31 42 Uterine carcinoma 42 22 44 22 Osteomyelitis, right foot pyogenes Staphylococcus aureus Urinary tract E. coli (U) None Urnary tract Osteomyelitis tibia Soft tissue, left forearm 49 8 days Meningitis a W, Wound; U, urine; CSF, cerebral spinal fluid. TABLE 5. Adverse reactions to moxalactam Disorder Patient no. Total Hypersensitivity Eosinophilia 23, 41a 2 Pruritus 31 1 Fever 27 1 Hepatotoxicity 4, 6, 9, 12, 13, 17, 19, 11 37,39,40,43 Anemia 5 1 Anorexia 42 1 Oral candidiasis 47 1 Confusion 21, 41a 2 Total 19a a Patient 41 is listed in two categories. E. coli (U) Pseudomonas maltophilia P. aeruginosa Acinetobacter calcoaceticus Aeromonas hydrophilia Enterobacter cloacae E. coli (CSF) Debridement None Debridement Removal of infected plate, left radius None 14 Unevalua- Drug ble reaction 10 9 107 53 22 was three times nornal. The patient was discharged, and a follow-up determination was not obtained. Patient 21 developed perinephric abscess and renal insufficiency after surgery for carcinoma of the cervix. During moxalactam therapy renal insufficiency improved, but serum alkaline phosphatase increased from a pretreatment value of 156 IU/liter (1.5 times normal) to 413 IU/liter. One month after discontinuation of moxalactam, the alkaline phosphatase had increased to 808 IU/liter; by 3 months, the level had fallen to 261 IU/liter. Shortly afterwards, the patient died of underlying disease.
94 LIVINGSTON ET AL. Eosinophilia of 8 and 11%, respectively, was noted in two patients. Patient 27 developed drug fever on the 11th day of therapy, and fever resolved after discontinuation of drug 3 days later. Patient 31 developed pruritus, without eosinophilia or rash, which responded partially to an oral antihistamine. However, the pruritus did not fully resolve until 1 month after completion of antibiotic therapy. Patient 42 experienced mild anorexia, which improved rapidly after moxalactam was stopped. One patient with mild chronic renal insufficiency experienced a decrease in hemoglobin, from 10.4 to 8.6 g/100 ml, during 9 days of treatment without evidence of hemolysis or a bleeding source. Patient 47 developed oral candidiasis. Two patients developed mental confusion during treatment with moxalactam. Patient 41, an 80-year-old woman with serious underlying disease, became disoriented while receiving 91 mg/ kg per day, almost twice the average dose used in the study. Patient 21, a 47-year-old woman with cervical carcinoma, became confused while receiving 50 mg/kg per day. Both patients continued to be confused for at least 1 month after moxalactam was discontinued. In addition, both continued to receive other drugs, though not in doses ordinarily considered excessive. Overall, 19 patients developed some adverse reaction while receiving moxalactam. In only one instance, however, did the reaction necessitate discontinuation of the drug (patient 27). Most of the side effects were mild and resolved after completion of therapy. As noted, the majority of the patients were older, were seriously ill before initiation of therapy, and had one or more underlying diseases; most were also receiving additional medications. Tolerance to parenteral administration. Patients who received intravenous moxalactam experienced no phlebitis and reported no pain during infusion. This is in agreement with an earlier published clinical study of moxalactam therapy (9). Patients 42 and 44 received deep intramuscular moxalactam for 3 and 6 weeks, respectively. No undue local reactions were experienced. Patient 42 noted mild dysesthesia on her right thigh where injections had been given repeatedly. The dysesthesia improved gradually when the injection sites were changed. Bacterial susceptibility. Table 6 lists the 71 bacterial isolates obtained from the 50 patients in this study. A previous study (3) indicated bacterial strains inhibited by 8,ug or less of moxalactam per ml may be considered susceptible, those with MICs of 16 to 32 jig/ml are intermediate, and those with MICs greater than or equal to 64 jig/ml are resistant. These MIC ANTIMICROB. AGENTS CHEMOTHER. TABLE 6. Susceptibilities of isolates to moxalactam No. of MIC (jg/ml) Organism isolates Median Range Gram-positive cocci Staphylococcus 3 6.25 (all) aureus 11 0.39 0.10-0.39 pneumornae 1 0.39 pyogenes Group B 2 6.25 Viridans 1 1.56 Gram-positive bacilli Diphtheroids 1 0.78 Lactobacillus 1 12.5 Gram-negative bacilli Escherichia coli 10 0.20 0.10-6.25 Klebsiella 5 0.39 0.39-0.78 pneumoniae Enterobacter sp. 4 0.78 0.10-6.25 Serratia 11 1.56 0.20-6.25 marcescens Proteus mirabilis 5 1.56 0.39-6.25 Pseudomonas 5 250 12.5-1,000 aerugmnosa P. maltophilia 1 1.56 P. fluore8cens 2 1.56 12.5-25 Aeromonas 1 250 hydrophilia Acinetobacter 2 25-50 calcoaceticus Haemophilus 3 0.39 0.05-0.78 influenzae Citrobacter 2 0.78, 6.25 diversus Total 71 values correspond to Kirby-Bauer disk zone sizes of ;23 mm (susceptible), 15 to 22 mm (intermediate), and c14 mm (resistant). By these criteria 54 of the 71 strains were susceptible, 15 were intermediate, and 2 were resistant. Three patients (15, 32, and 46) with P. aeruginosa infection caused by strains of intermediate susceptibility were treated with moxalactam alone. Two improved, and one patient (46) died suddenly while improving clinically. Patient 16 had disease caused by P. aeruginosa which became more resistant during therapy (MIC of 12.5,tg/ ml initially and 250,g/ml after treatment) and Serratia marcescens. Moxlactam was combined with an aminoglycoside to which the P. aeruginosa isolate was susceptible but to which the serratia was not. Patient 30 had polymicrobial bacteremia caused by pneumoniae and P. fluorescens. The latter was of intermediate susceptibility to moxalactam. Two patients, in addition to patient 16, demonstrated emergence of resistant P. aeruginosa during therapy with moxalactam. Patient 8, who had an indwelling Foley catheter and received
VOL. 20, 1981 moxalactam for serratia bacteremia, developed a subsequent urinary tract infection with P. aeruginosa resistant to moxalactam; it responded subsequently to tobramycin. Patient 34 presented with a pneumonia caused by Proteus mirabilis and Enterobacter aerogenes. After 10 days of treatment with moxalactam, the patient had clinically and radiologically improved, but P. aeruginosa resistant to moxalactam was cultured from sputum. No additional antibiotics were added, and the pneumonia resolved. We treated nine patients with infectious disorders caused by multiresistant gram-negative bacilli. Patients 1, 2, 3, 8, 16, 20, and 21 developed infection with a strain of Serratia marcescens resistant to amikiacin, gentamicin, tobramycin, carbenicillin, and cefoxitin. It is probable some of these cases represent a nosocomial outbreak caused by the same strain of serratia. Patient 42 had osteomyelitis, and one of the etiological bacteria, a strain of Pseudomonas maltophilia, was resistant to amikacin, gentamicin, tobramycin, cefoxitin, and carbenicillin and susceptible only to moxalactam. Patient 47 had pneumonia, and on multiple occasions Proteus mirabilis and Klebsiella pneumoniae were cultured from sputum. The klebsiella was resistant to gentamicin, tobramycin, cefoxitin, cefamandole, and carbenicillin and susceptible only to amikacin and moxalactam. CLINICAL EVALUATION OF MOXALACTAM 95 DISCUSSION Moxalactam is one of a number of so-called third-generation cephalosporin antimicrobial agents which have recently become available for clinical trials. These compounds, which include cefoperazone, ceforanide, cefotaxime, ceftizoxime, and cefsulodin, exhibit a significantly increased spectrum of activity against many gramnegative bacilli, particularly Enterobacteriaceae (10, 12, 19). In addition, they broaden the spectrum of cephalosporins to include P. aeruginosa, serratia, and some acinetobacter strains. These third-generation cephalosporins are, in general, less active than penicillin G and semisynthetic penicillins against gram-positive microorganisms such as staphylococci and streptococci (18, 19). However, disease caused by these latter microorganisms has been sucessfully treated with moxalactam. Moxalactam has been shown to be effective in vitro against multiply resistant gram-negative bacilli (10) and against anaerobic microorganisms such as Bacteroides fragilis and Clostridium perfringens (4, 8, 12). It is also active against strains of Legionella (7). Moxalactam is not active against enterococci (11). A previous report from this laboratory (6) confirmed the effectiveness of moxalactam in vitro against gram-negative isolates from this institution and encouraged us to use the agent in a clinical trial. For the most part, the microorganisms isolated from the patients included in this study were highly susceptible to moxalactam. By the current criteria for susceptibility, 54 of 72 strains were susceptible, 15 were intermediate, and only 2 were resistant. Moxalactam was especially useful in the management of disease caused by a multiresistant strain of Serratia marcescens. The patients treated in this study are representative of the complex clinical problems encountered in a tertiary care institution. Many suffered serious underlying disorders, including 7 which could be classified as ultimately fatal and 43 as nonfatal. No patients with rapidly fatal underlying disease were treated with moxalactam. The infectious disorders included pneumonia, infective endocarditis, urinary tract infection with and without bacteremia, intraabdominal infection, soft tissue infection, meningitis, and osteomyelitis. Moxalactam should not be used for therapy of any bacterial infectious disorder when a safer, narrower-spectrum, less expensive agent is available. For example, in patients with presumed pneumococcal pneumonia, penicillin remains the agent of choice. Patients with pneumococcal disease who were begun on moxalactam when the precise etiology was unclear were continued on this agent to determine efficacy and toxicity. In practice, if a broad-spectrum agent is initially chosen for therapy and pneumococcus is found to be the etiological agent, one should change to standard therapy. Results of studies of moxalactam therapy at 12 different medical centers in almost 440 patients were recently presented (D. Bauman, B. Holmes, B. Pollack, R. Beville, and W. J. Mogabgab, Program Intersci. Conf. Antimicrob. Agents Chemother. 20th, New Orleans, La., abstr. no. 370, 1980; S. A. Gall, W. A. Addison, and G. B. Hill, 20th ICAAC, abstr. no. 373; H. Giamarellou, J. Tsagarakis, and G. K. Daikos, 20th ICAAC, abstr. no. 364; M. Kramer, W. El- Sadr, P. Tee, A. Pollock, M. S. Simberkoff, and J. J. Rahal, Jr., 20th ICAAC, abstr. no. 374; A. Lentnek, L. Kidd, and R. Ryan, 20th ICAAC, abstr. no. 369; R. V. McCloskey and R. Goren, 20th ICAAC, abstr. no. 366; R. G. Penn, L. C. Preheim, C. C. Sanders, and W. E. Sanders, Jr., 20th ICAAC, abstr. no. 375; C. Perlino, D. Jones, and S. McGlohn, 20th ICAAC, abstr. no. 372; R. Platt, S. L. Ehrlich, J. E. Pennington, and E. H. Kass, 20th ICAAC, abstr. no. 371; C. B. Savitch, R. Lowe, R. Jacobs, J. E. Conte, Jr., S. Barriere,
96 LIVINGSTON ET AL. and J. Mills, 20th ICAAC, abstr. no. 367; S. Srinivasan, E. L. Francke, and H. C. Neu, 20th ICAAC, abstr. no. 365; L. S. Young, T. 0. Kurtz, D. Winston, and R. W. Busuttil, 20th ICAAC, abstr. no. 368). The infectious disorders included lower respiratory infection in 175 patients, urinary tract infection in 102, and bacteremia in approximately 50. In general, the outcome of moxalactam therapy in these preliminary reports was good, with an 85% overall cure rate. Side effects reported included eosinophilia, mild abnormalities of liver function, and mild intolerance to parenteral therapy. An important problem described in some of the reports was the emergence during therapy of resistant bacteria, particularly strains of P. aeruginosa. Only one patient in our study, patient 16, demonstrated a change in the susceptibility of an infecting bacterial species repeatedly isolated from bone during a treatment course of 3 months. Superinfection occurred in one other case (42), a patient who also received a prolonged course of therapy. The results in our 23 patients with pneumonia together with the 175 cases previously reported confirm the general effectiveness of moxalactam in lower respiratory tract infection. It remains unclear whether superinfection with resistant microorganisms or emergence of resistance among bacteria already present will be a serious problem during therapy with moxalactam. In our study, these complications occurred in three patients. The bacteriological and clinical outcomes of our other patients treated with moxalactam were also very good. Bacteriological cure was documented in 45 of 50 patients, and clinical cure was achieved in 48 of 50. We were particularly gratified by the response to moxalactam therapy of patients with bacteremic illnesses including pyelonephritis, serious intraabdominal disease, burns, and infective endocarditis. Clinical cures were obtained in 16 of our 17 patients. We generally treated bacteremic patients for at least 2 weeks unless there was evidence of intravascular infection. The effectiveness of moxalactam in our one patient with gram-negative meningitis is noteworthy. Reports of therapy of experimental meningitis in rabbits and infant rats (5, 16) and in six patients with gram-negative meningitis (13; Kramer et al., 20th ICAAC, abstr. no. 374; Srivivasan et al., 20th ICAAC, abstr. no. 365) ANTIMICROB. AGENTS CHEMOTHER. have provided optimism among pediatricians that moxalactam will provide an effective therapy for infants with gram-negative bacterial meningitis. Cerebrospinal fluid levels of moxalactam after intravenous administration to neonates appear to provide quite adequate concentrations against most gram-negative bacilli (17). In contrast, a recent abstract describes a patient who developed pneumococcal meningitis complicating pneumococcal pneumonia while receiving moxalactam therapy (Perlino et al., 20th ICAAC, abstr. no 372). In our judgment, moxalactam should not be used alone for treatment of meningeal infection unless susceptibility of the infecting microorganism can be documented and adequate cerbrospinal fluid levels can be confirmed by laboratory testing. The toxicity of moxalactam may be compared and contrasted with that associated with cefamandole therapy since these two antimicrobial agents are relatively similar. Previous studies with cefamandole have indicated phlebitis associated with intravenous administration in 1 to 10% of patients. Eosinophilia occurred in 15% of patients in one study (15), and abnornal liver function tests were present in 14 to 24%. In this series, moxalactam administration was associated with no instance of phlebitis, whereas eosinophila and abnormal liver function tests were found in 4 and 22% of patients, respectively. Importantly, moxalactam therapy had to be discontinued in only one patient. The broad antibacterial spectrum of moxalactam, its relative lack of toxicity, and the encouraging results of clinical trials such as this one will probably result in widespread consideration of the agent once it is released for general use. An important clinical decision in the management of patients with suspected or proven bacterial disorders will be whether or not moxalactam alone is adequate therapy before the infecting bacteria are isolated and identified. Patients who were granulocytopenic and therefore at risk for life-threatening disease caused by P. aeruginosa were not recruited into this clinical trial. Thirty percent of the strains of P. aeruginosa from this institution have MICs of moxalactam greater than 32,tg/ml. The number of patients in this series with infections involving P. aeruginosa is small, and several of these required treatment with aminoglycosides due to resistance to moxalactam. As a result, we do not feel justified in using moxalactam alone in granulocytopenic patients, nor would we recommend the use of moxalactam alone for other patients likely to have pseudomonas disease. We did not investigate in vitro or in vivo synergism or antagonism between moxalactam and other antimicrobial agents, such as the aminoglycosides. Although the combination of moxalactam and an aminoglycoside may be quite active against strains of P. aeruginosa with MICs greater than 32 yg/ml, until in vitro and in vivo data are available, "standard" regimens against pseu-
VOL. 20, 1981 domonas such as carbenicillin or ticarciliin combined with gentamicin or tobramycin should be used. We also advise that moxalactam therapy not be used for patients with serious intravascular infections caused by gram-positive microorganisms. There is no good clinical evidence presently available to indicate how effective moxalactam will be in this group. Patients with prosthetic valve endocarditis caused by Staphylococcus epidermidis or S. aureus are an especially vexing problem and should not routinely be treated with moxalactam until its efficacy in these disorders has been proven. In contrast, moxalactam may prove very useful in bacterial disorders caused by more than one species. Cellulitis and intraabdominal infections due to aerobic and anaerobic bacteria should respond well to this agent alone, eliminating the necessity for aminoglycosides to treat reigstant aerobic gram-negative bacilli and clindamycin or chloramphenicol to treat Bacteroides fragilis. Many of the patients described in this report had disorders caused by bacteria which are susceptible to older and clinically proven agents. Penicillin G remains the drug of choice for pneumococcal disease, and urinary tract infection caused by "susceptible" E. coli can be managed with ampicillin. Moxalactam will probably be most valuable if clinicians restrict its use to initial therapy of bacterial disorders due to potentially resistant microorganisms and for follow-up treatment of difficult disorders such as pneumonia, osteomyelitis, and intraabdominal disease caused by resistant or multiple bacteria. ACKNOWLEDGMENTS We express our gratitude to J. A. Hafuer, clinical research coordinator of The Lilly Research Laboratories, and to Susan J. Lamb and Madeline Webb for their excellent secretarial assistance. This investion was supported in part by funds from Eli Lilly Research Laboratories, Indianapolis, Ind. LITERATURE CITED 1. Anhalt, J. P., L. D. Sabath, and A. L Barry. 1980. 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